Ligands for mineralocorticoid receptor (MR) and methods for screening for or designing MR ligands
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United States of America Patent
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Issued Date -
May 17, 2007
app pub date -
Nov 14, 2006
filing date -
Nov 15, 2005
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Abstract
The inventors disclose a 1.95 .ANG. crystal structure of the MR ligand binding domain containing a single C808S mutation bound to a corticosterone and the fourth LXXLL motif of steroid receptor coactivator-1 (SRC1-4). The inventors demonstrate that SRC1-4 is the most potent MR-binding motif and mutations that disrupt the MR/SRC1-4 interactions abolish the ability of the full-length SRC1 to coactivate MR. The structure also reveals a compact steroid binding pocket with a unique topology that is primarily defined by key residues of helices 6 and 7. Also described are novel ligands for MR, methods for screening for and designing novel MR ligands, and methods for treating MR-related diseases.
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